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    Mice lacking Tbk1 activity exhibit immune cell infiltrates in multiple tissues and increased susceptibility to LPS-induced lethality

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    Authors
    Marchlik, Erica
    Thakker, Paresh
    Carlson, Thaddeus
    Jiang, Zhaozhao
    Ryan, Mark
    Marusic, Suzana
    Goutagny, Nadege
    Kuang, Wen
    Askew, G. Roger
    Roberts, Victoria
    Benoit, Stephen
    Zhou, Tianhui
    Ling, Vincent
    Pfeifer, Richard
    Stedman, Nancy
    Fitzgerald, Katherine A.
    Lin, Lih-Ling
    Hall, J. Perry
    Show allShow less
    UMass Chan Affiliations
    Department of Medicine, Division of Infectious Diseases and Immunology
    Document Type
    Journal Article
    Publication Date
    2010-12-24
    Keywords
    Animals
    Chemokine CCL2
    Female
    Interferon Regulatory Factor-3
    Interferon-beta
    Lipopolysaccharides
    Male
    Mice
    Mice, Inbred C57BL
    Monocytes
    Protein-Serine-Threonine Kinases
    Immunology and Infectious Disease
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    Metadata
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    Link to Full Text
    http://dx.doi.org/10.1189/jlb.0210071
    Abstract
    TBK1 is critical for immunity against microbial pathogens that activate TLR4- and TLR3-dependent signaling pathways. To address the role of TBK1 in inflammation, mice were generated that harbor two copies of a mutant Tbk1 allele. This Tbk1(Delta) allele encodes a truncated Tbk1(Delta) protein that is catalytically inactive and expressed at very low levels. Upon LPS stimulation, macrophages from Tbk1(Delta/Delta) mice produce normal levels of proinflammatory cytokines (e.g., TNF-alpha), but IFN-beta and RANTES expression and IRF3 DNA-binding activity are ablated. Three-month-old Tbk1(Delta/Delta) mice exhibit mononuclear and granulomatous cell infiltrates in multiple organs and inflammatory cell infiltrates in their skin, and they harbor a 2-fold greater amount of circulating monocytes than their Tbk1(+/+) and Tbk1(+/Delta) littermates. Skin from 2-week-old Tbk1(Delta/Delta) mice is characterized by reactive changes, including hyperkeratosis, hyperplasia, necrosis, inflammatory cell infiltrates, and edema. In response to LPS challenge, 3-month-old Tbk1(Delta/Delta) mice die more quickly and in greater numbers than their Tbk1(+/+) and Tbk1(+/Delta) counterparts. This lethality is accompanied by an overproduction of several proinflammatory cytokines in the serum of Tbk1(Delta/Delta) mice, including TNF-alpha, GM-CSF, IL-6, and KC. This overproduction of serum cytokines in Tbk1(Delta/Delta) mice following LPS challenge and their increased susceptibility to LPS-induced lethality may result from the reactions of their larger circulating monocyte compartment and their greater numbers of extravasated immune cells.
    Source
    J Leukoc Biol. 2010 Dec;88(6):1171-80. Epub 2010 Jul 22. Link to article on publisher's site
    DOI
    10.1189/jlb.0210071
    Permanent Link to this Item
    http://hdl.handle.net/20.500.14038/34884
    PubMed ID
    20651301
    Related Resources
    Link to Article in PubMed
    ae974a485f413a2113503eed53cd6c53
    10.1189/jlb.0210071
    Scopus Count
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